Clinical trialPhase 3Stomach cancer

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial

Lancet · 2023698 patients (350 pembrolizumab and 348 placebo)

Janjigian YY, Kawazoe A, Bai Y, et al. Lancet. 2023. 402:2197-2208

Study type: Clinical trial
Study name: KEYNOTE-811
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial at 168 centres in 20 countries (1:1 randomisation)
Sample size: 698 patients (350 pembrolizumab and 348 placebo)
Source: Lancet · 2023
Trial registration: NCT03615326

In plain words

In advanced HER2-positive stomach cancer, the standard first treatment for years was trastuzumab combined with chemotherapy. KEYNOTE-811 showed that adding the immunotherapy drug pembrolizumab to this combination shrinks the tumour in more patients and delays the growth of the disease. In the final analysis, published in 2024, patients in the pembrolizumab group lived on average about 3 months longer, and this benefit is seen in patients whose tumour has PD-L1 (CPS 1 or more). Side effects were slightly more common, but no new safety concerns were seen.

Key results

10.0 vs 8.1 months

Median progression-free survival (second interim analysis)

HR 0.72 (95% CI 0.60–0.87); p=0.0002

20.0 vs 16.8 months

Median overall survival (third interim analysis)

HR 0.84 (0.70–1.01); did not reach the significance criterion at this stage

20.0 vs 16.8 months

Median overall survival (final analysis, NEJM 2024)

HR 0.80 (95% CI 0.67–0.94); p=0.0040; median follow-up 50.2 months

20.1 vs 15.7 months

Overall survival in PD-L1 CPS ≥1 (final analysis)

HR 0.79 (0.66–0.95); p=0.0062 (nominal)

58% vs 51%

Treatment-related grade 3 or higher adverse events

204 of 350 vs 176 of 346 patients

Drugs in this study:Capecitabine (Xeloda)Cisplatin (Platinol)Fluorouracil (5-FU)Oxaliplatin (Eloxatin)Pembrolizumab (Keytruda)Trastuzumab (Herceptin)

Dose and schedule cards

Pembrolizumab + trastuzumab + chemotherapy (KEYNOTE-811 trial)

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-positive; FDA label: PD-L1 CPS ≥1Cycle length: Every 21 daysOn the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-positive

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-positive; FDA label: PD-L1 CPS ≥1

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV (30 min), before trastuzumab and chemotherapy	Day 1
Trastuzumab	First dose 8 mg/kg, then 6 mg/kg	IV	Day 1
FP
Cisplatin	80 mg/m² (maximum 6 cycles)	IV	Day 1
Fluorouracil	800 mg/m² per day	IV, continuous infusion	Days 1–5
Or CAPOX
Oxaliplatin	130 mg/m² (maximum 6 to 8 cycles)	IV	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14

Cycle length: Every 21 days
Duration: Pembrolizumab until progression, unacceptable toxicity or a maximum of 24 months; trastuzumab until disease progression

Doses from the FDA label for pembrolizumab (description of the KEYNOTE-811 trial).

On the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-positive

HER2-positive adenocarcinoma: trastuzumab + cisplatin + fluoropyrimidine, ± pembrolizumab (ToGA and KEYNOTE-811)

Advanced HER2-positive adenocarcinoma; trials and FDA label in gastric and gastroesophageal junction tumours; add pembrolizumab if PD-L1 CPS ≥1Cycle length: Every 21 daysOn the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Advanced HER2-positive adenocarcinoma; trials and FDA label in gastric and gastroesophageal junction tumours; add pembrolizumab if PD-L1 CPS ≥1

Drug	Dose	Route	Schedule
Trastuzumab	First dose 8 mg/kg (90 minutes), then 6 mg/kg (30–90 minutes)	IV	Day 1
Cisplatin	80 mg/m²	IV	Day 1 (6 cycles)
Capecitabine or fluorouracil	Capecitabine 1000 mg/m² twice daily (Days 1–14) or fluorouracil 800 mg/m²/day continuous infusion (Days 1–5)	Oral / IV	Days 1–14 or 1–5
Pembrolizumab (if CPS ≥1)	200 mg (or 400 mg every 6 weeks)	IV, before trastuzumab and chemotherapy	Day 1

Cycle length: Every 21 days
Duration: Chemotherapy for 6 cycles; trastuzumab until disease progression; pembrolizumab for up to 24 months

Doses from the FDA labels for trastuzumab (ToGA) and pembrolizumab (KEYNOTE-811; CAPOX was also permitted in this trial: oxaliplatin 130 mg/m² on Day 1 for 6 to 8 cycles + capecitabine). Monitor LVEF before starting and every 3 months; withhold trastuzumab for an absolute decrease of 16% or more, or for an LVEF below the lower limit of normal with a decrease of 10% or more.

On the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + trastuzumab + chemotherapy

Pembrolizumab 200 mg IV on day 1 every 3 weeks, for up to 35 cycles or until disease progression, unacceptable toxicity or withdrawal; with trastuzumab IV (loading dose 8 mg/kg, then 6 mg/kg every 3 weeks) and chemotherapy of investigator's choice:

FP: cisplatin 80 mg/m² IV on day 1 + fluorouracil 800 mg/m² per day as a continuous infusion on days 1 to 5, every 3 weeks; or
CAPOX: oxaliplatin 130 mg/m² IV on day 1 + capecitabine 1000 mg/m² orally twice daily on days 1 to 14, every 3 weeks;
in Japan: SOX (oxaliplatin 130 mg/m² + oral S-1 twice daily on days 1 to 14, dosed by body surface area).

2Placebo + trastuzumab + chemotherapy (control group)

IV placebo every 3 weeks with trastuzumab and FP, CAPOX or SOX chemotherapy at the same doses and schedule.

Source of the regimen details: Abstract of the paper (Lancet 2023: pembrolizumab 200 mg every 3 weeks for up to 35 cycles) and ClinicalTrials.gov NCT03615326 (doses of trastuzumab, FP, CAPOX and SOX)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults (18 years or older) with locally advanced unresectable or metastatic HER2-positive (IHC ‎3+‎ or IHC ‎2+‎ with positive ISH, centrally reviewed) gastric or gastro-oesophageal junction adenocarcinoma, with no previous first-line therapy, measurable disease and ECOG performance status 0 or 1.

Endpoints

Dual primary endpoints: progression-free survival (PFS) and overall survival (OS), by intention-to-treat analysis.

Other endpoints: objective response (reported at the first interim analysis) and safety.

Safety and side effects

Treatment-related grade 3 or higher adverse events occurred in 58% of the pembrolizumab group and 51% of the placebo group. Deaths from treatment-related adverse events were reported in 4 patients (1%) and 3 patients (1%). Most common treatment-related adverse events of any grade: diarrhoea (47% versus 42%), nausea (44% versus 44%) and anaemia (31% versus 33%). In the final analysis, grade 3 to 5 adverse events occurred in 59% versus 51%, and no new safety concerns were seen.

Clinical significance and place in guidelines

Based on the interim results of KEYNOTE-811, in 2021 the FDA granted accelerated approval to pembrolizumab with trastuzumab and fluoropyrimidine-‎ and platinum-containing chemotherapy for first-line treatment of advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma; in 2023 this approval was restricted to tumours with PD-L1 CPS ≥1, and in March 2025, after the final analysis, it was converted to full (traditional) approval. The final overall survival analysis (Janjigian et al., N Engl J Med 2024;391:1360-1362; DOI: 10.1056/NEJMc2408121) showed a significant improvement in overall survival (HR 0.80). The NCCN guideline (version 2.2025) lists this combination as a category 1 preferred first-line option for HER2-positive patients with CPS ≥1.

Limitations

The main results of this paper come from interim analyses, and at the time of publication overall survival had not yet reached the significance criterion (the final analysis was published later). Few patients had PD-L1 CPS below 1, and the benefit in this group is unclear. Grade 3 or higher adverse events were more frequent in the pembrolizumab group. The study was funded by the manufacturer.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.